Mycobacterium tuberculosis, the causative agent of human tuberculosis infects approximately one-third of the world's population and kills nearly two million people each year. New strategies of the treatment of existing disease and improved vaccination methods to prevent new infections will require a greater understanding of the mechanisms used by this pathogen to persist in the host and cause disease. Unlike many other bacterial pathogens, M. tuberculosis interacts with the host largely through the secretion of a wide variety of complex small molecules. Using a new genetic methodology, we have identified secondary metabolite biosynthetic pathways and large multisubunit transport systems that function in concert to promote bacterial growth in vivo and disease progression. Using a panel of M. tuberculosis mutants that lack either transport systems of biosynthetic genes, we will identify the novel compounds that mediate interactions between the bacterium and host (Aim 1). By characterizing the altered interaction between these mutants and the host macrophage, we will determine the the specific roles played by these systems during infection (Aim 2), Finally, we will dissect the structure and functions of individual transporter components to identify virulence-specific adaptations that explain some of the unique biology of this infection (Aim 3).